Submission Details

Design Rationale:

Fluoro-substitution of at isoquinoline C6/7 is well tolerated and is a tactic for reducing metabolism off the P1-isoquinoline. To date only 6-fluoroisoquinolines have been synthesized although C6 appears to sense the electron-withdrawing effect of isoquinoline nitrogen more strongly than C7 (pKa values of 6-aminoisoquinoline and 7-aminoisoquinoline are 7.2 and 6.2 respectively; see https://doi.org/10.1021/jo00972a031 ). As such, C7/C8 may be inherently more vulnerable than C5/C6. In any case it would be prudent compare the protection provided by 6-fluoro and 7-fluoro substituents. I have generated a number of options for the design team’s consideration but make no specific recommendations.

Other Notes:

The submission consists mainly of 6-fluoroisoquinoline designs although some 6-fluoroisoquinolines have been included if they had not already been registered (apologies in advance for any duplicates). Protein-ligand complexes were energy minimized using Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at the positions of the crystallographic ligand). The X11612 A chain was used for modelling designs 1-6 and the P0157 A chain was used for modelling designs 7-11. The PDB file associated with this submission contains the following: [1] X11612 A chain [2] X11612 A chain crystallographic ligand (MAT-POS-b3e365b9-1) [3-8] Designs 1-6 [9] P0157 A chain [10] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [11-15] Designs 7-11

Inspired By:

PET-UNK-5d7c542f-1

EDJ-MED-611d11e7-6

EDG-MED-5d232de5-1

MAT-POS-64942dd0-2

JIN-POS-6dc588a4-11